These recommendations update previous CDC/American Thoracic
Society (ATS) recommendations for the treatment of tuberculosis
(TB) among adults and children (1). The most notable changes are in
response to the increasing prevalence of drug-resistant TB in the
United States. These recommendations include the need for a) in
vitro drug susceptibility testing of Mycobacterium tuberculosis
isolates from all patients and reporting of these results to the
health department, b) initial four-drug regimens for the treatment
of TB, and c) initial directly observed therapy for persons with
TB. Adherence to these recommendations will help prevent the
occurrence of more cases of drug-resistant TB, reduce the
occurrence of treatment failure, and reduce the transmission of TB
in the United States.

INTRODUCTION

The number of tuberculosis (TB) cases reported in the United
States has declined from more than 84,000 cases in 1953 to 22,255
cases in 1984. However, since 1984 dramatic changes in TB morbidity
trends have occurred, and these changes jeopardize the control of
TB. From 1985 through 1991, reported TB cases increased 18% --
representing approximately 39,000 more cases than expected had the
previous downward trend continued (CDC, unpublished data). The
excess number of cases is due to many factors, including the human
immunodeficiency virus (HIV) epidemic, a deterioration in the
health-care infrastructure, and increases in the number of cases
among foreign-born persons.

The recent emergence of drug-resistant TB also has become a
serious concern. For example, in New York City in 1991, 33% of TB
cases were resistant to at least one drug, and 19% were resistant
to both isoniazid (INH) and rifampin (RIF) (2) -- the two most
effective drugs available for treating TB. Resistance to both INH
and RIF substantially increases the cost and duration of treatment,
while decreasing the efficacy.

Based on surveys of all TB cases reported to CDC during the
first quarter of 1991, cases of TB resistant to one or more drugs
were reported from all 10 Health and Human Services/Public Health
Service regions of the United States. Moreover, during the period
1982-1986, 0.5% of new TB cases were resistant to both INH and RIF,
whereas preliminary analysis of data for the first quarter of 1991
suggests that this proportion was about 3%. Among recurrent cases,
3% were resistant to both drugs during the period 1982-1986,
compared with 6.9% in 1991.

Outbreaks of multidrug-resistant TB (MDR-TB) -- resistant to
both INH and RIF, as well as to other drugs -- have occurred in a
variety of institutional settings. From 1990 through 1992, CDC has
investigated nine outbreaks of MDR-TB in hospitals and prison
facilities in Florida and New York (3-5). These outbreaks have been
characterized by a high prevalence of HIV infection among the
outbreak cases, range 20%-100%; a high mortality rate among
patients with MDR-TB, range 72%-89%; a short median interval
between TB diagnosis and death, range 4-16 weeks; and transmission
of MDR-TB to health-care and correctional facility workers, at
least 17 of whom have developed active MDR-TB.

Drug-resistant tubercle bacilli are transmitted in the same
manner as drug-susceptible organisms. A study comparing infection
rates among contacts of TB patients suggested that the likelihood
of transmission was similar for both drug-resistant and
drug-susceptible organisms (6). In institutional TB outbreaks
investigated from 1991 to 1992, tuberculin skin-test conversions
among health-care workers were more likely to be associated with
exposure to patients with drug-resistant organisms than to patients
with drug-susceptible organisms (3) -- probably reflecting the
persistent infectiousness of patients with unrecognized
drug-resistant TB who were not on effective therapy.

Mycobacterium tuberculosis becomes drug resistant through
random, spontaneous genetic mutation. The proportion of naturally
occurring resistance has been established for several of the
primary anti-TB drugs: RIF, 1/108; INH and streptomycin (SM),
1/106; and ethambutol, (EMB) 1/104. Assuming that the mutations are
independent, the likelihood of an organism spontaneously developing
resistance to more than one drug is the product of probabilities;
for example, the probability of INH and RIF resistance occurring in
the same organism is 1/108 times 1/106 (1/1014). Because the total
number of bacilli in an infected person, even with advanced
cavitary disease, does not approach this number (1014), spontaneous
evolution of MDR tubercle bacilli occurs infrequently.

TREATMENT

Because administration of a single drug often leads to the
development of a bacterial population resistant to that drug,
effective regimens for the treatment of TB must contain multiple
drugs to which the organisms are susceptible. When two or more
drugs are used simultaneously, each helps prevent the emergence of
tubercle bacilli resistant to the others. However, when the in
vitro susceptibility of a patient's isolate is not known -- which
is generally the case at the beginning of therapy -- selecting two
agents to which the patient's isolate is likely to be susceptible
can be difficult. Improper selection of drugs for the treatment of
drug-resistant TB (i.e., providing only one drug to which most
organisms are susceptible) may subsequently result in the
development of additional drug-resistant organisms.

A four-drug regimen with INH, RIF, pyrazinamide (PZA), and SM
or EMB is preferred for the initial, empiric treatment of TB
(Tables 1,2). When adherence with the regimen is assured, such as
with directly observed therapy (DOT), the four-drug regimen is
highly effective even for INH-resistant organisms (7). Based on the
prevalence and characteristics of drug-resistant organisms, at
least 95% of patients will receive an adequate regimen (at least
two drugs to which their organisms are susceptible) if this
four-drug regimen is used at the beginning of therapy (CDC,
unpublished data). Even with susceptible organisms, sputum
conversion is accomplished more rapidly from positive to negative
with a four-drug regimen than with a three-drug regimen of INH,
RIF, and PZA (8). DOT is more easily managed with the four-drug
regimen since it can be administered intermittently 3 times/week
from the beginning of therapy (7). The four-drug regimen also can
be administered 2 times/week following a 2-week induction phase of
daily therapy (9). Finally, a patient who is treated with the
four-drug regimen, but who defaults therapy is more likely to be
cured and not relapse when compared with a patient treated for the
same length of time with the three-drug regimen.

RECOMMENDATIONS

To avoid the emergence of drug-resistant organisms, the
Advisory Council for the Elimination of Tuberculosis (ACET)
recommends the following approach to beginning therapy for TB.
Susceptibility Testing

All persons with TB from whom M. tuberculosis is isolated
should have drugsusceptibility testing performed on their first
isolate; these results should be reported promptly to the
health-care provider and to the health department.

Such testing will provide the basis for clinical therapeutic
decisions. In addition, surveillance of drug-susceptibility reports
will help identify emerging drug resistance and help monitor
control efforts in areas where resistance is already established.
Drug-susceptibility testing also should be performed on additional
isolates from patients whose cultures fail to convert to negative
within 3 months of beginning therapy, or if there is clinical
evidence of failure to respond to therapy. To monitor changes in
drug susceptibility patterns in the United States, the "Report of
Verified Cases of Tuberculosis" reporting form has been revised to
include a section relating to drug susceptibility results from the
initial isolate for all reported TB cases.
Initial Regimen

The initial treatment of TB should include four drugs. During
the first 2 months, the drug regimen should include INH, RIF, PZA,
and EMB or SM. When drug susceptibility results are available, the
regimen should be altered as appropriate. This regimen should be
administered to all patients unless the likelihood of INH or RIF
resistance is low.
General Principles

Analysis of local rates of drug resistance provides the best
basis for determining when the four-drug regimen might not be
necessary. Local data may indicate that the population in general
is at low risk for drug resistance or that specific and definable
subgroups in the population can be defined that are at low risk for
drug resistance. In the past, when national INH-resistance rates
were about 4% and declining (10), two- and three-drug regimens were
considered adequate. Community rates of INH resistance less than 4%
may be an indication that an initial regimen with fewer than four
drugs may be acceptable. However, continued surveillance of drug
susceptibility patterns is necessary to ensure that low rates of
drug resistance continue.

Institutions (e.g., health-care and correctional facilities)
that are experiencing outbreaks of TB resistant to INH and RIF or
that are resuming treatment for a patient with a prior history of
anti-TB therapy may need to begin five-drug or six-drug regimens as
initial therapy. These regimens should include the four-drug
regimen and at least three drugs to which the suspected
multidrug-resistant strain may be susceptible.

When the results of drug susceptibility tests become
available, regimens should be specifically defined on the basis of
those results. For example, patients whose TB organisms are
susceptible to INH and RIF should receive a regimen of INH and RIF
for a full 6 months, supplemented with PZA during the first 2
months. The treatment regimen of patients with drug-resistant
organisms should be determined in consultation with physicians
experienced in the treatment of drug-resistant TB.

When results of drug susceptibility tests are not available,
either due to a failure to perform the tests or a failure of the
test to yield definitive results, the decision to modify therapy
should be based on the probability of drug resistance. Where the
prevalence of drug resistance is sufficiently substantial to
justify starting all patients on the four-drug regimen (i.e., a
prevalence of INH resistance greater than or equal to 4%), PZA
should be discontinued at 8 weeks, but EMB or SM should be
continued (along with INH and RIF) for a total of 6 months.
Immunosuppressed Patients

HIV infection and other factors that compromise a patient's
immune system are important considerations when clinicians select
the most effective regimen for the treatment of TB. These factors
are particularly important with drug-resistant TB because of the
potential for rapid disease progression and death when patients
receive inadequate treatment. Because data from controlled clinical
trials are not available to determine if a 6-month regimen is
adequate treatment for HIV-infected patients with TB, ACET
recommends that such patients be treated for a total of 9 months
and for at least 6 months after sputum conversion (11). No evidence
suggests that intermittent therapy -- 2 times/week or 3 times/week

will not be as effective for the treatment of TB among
HIV-infected persons when compared with TB treatment for persons
who are not HIV positive.

If drug susceptibility results are not available, EMB or SM
should be continued for the entire course of therapy because of the
risk of rapid disease progression while the patient is on
inadequate therapy.
Treatment of Extrapulmonary TB

Regimens that are adequate for treating adults and children
with pulmonary TB also should be effective in treating
extrapulmonary disease. However, some experts extend the duration
of therapy to 9 months for patients with disseminated disease,
miliary disease, disease involving the bones or joints, or
tuberculous lymphadenitis. The use of adjunctive therapies, such as
surgery and corticosteroids, may be beneficial (1).
Treatment of Infants and Children

Infants and children with TB should be treated with the same
regimens recommended for adults; however, dosage may vary for some
drugs (Table 2). Further, EMB is generally not used for children
whose visual acuity cannot be monitored (e.g., those less than 6
years of age); SM is an alternative. The inclusion of EMB in the
treatment regimen should be considered, however, for all children
with organisms resistant to other drugs when susceptibility to EMB
has been demonstrated or when susceptibility is likely. Because the
risk of dissemination of TB is greater among infants than adults,
prompt and vigorous treatment should begin as soon as the diagnosis
is suspected.
Treatment of TB During Pregnancy

Effective therapy for TB is essential for pregnant women with
TB. However, the treatment regimen must be adjusted since SM may
cause congenital deafness. SM is the only licensed anti-TB drug
documented to have harmful effects on the fetus (1). Routine use of
PZA also is not recommended during pregnancy because the risk of
teratogenicity has not been determined. In addition, since the
6-month treatment regimen cannot be used and a minimum of 9 months
of therapy is recommended, the preferred initial treatment regimen
is INH, RIF, and EMB. If resistance to other drugs is likely and
susceptibility to PZA also is likely, the use of PZA should be
considered and the risks and benefits of the drug carefully
weighed. Because the small concentrations of anti-TB drugs in
breast milk do not produce toxicity in the nursing newborn, breast
feeding should not be discouraged. Further, because these drug
levels are so low in breast milk they cannot be relied upon for
either prophylaxis or therapy for nursing infants.
Directly Observed Therapy (DOT)

A major cause of drug-resistant TB and treatment failure is
patient nonadherence to prescribed treatment. Treatment failure and
drug-resistant TB can be life-threatening and pose other serious
public health risks because they can lead to prolonged
infectiousness and increased transmission of TB in the community.
DOT is one method of ensuring adherence; it requires that a
health-care provider or other designated person observe while the
patient ingests anti-TB medications.

DOT should be considered for all patients because of the
difficulty in predicting which patients will adhere to a prescribed
treatment regimen. Decisions regarding the use of expanded or
universal DOT should be based on a quantitative evaluation of local
treatment completion rates. If the percentage of patients who
complete therapy within 12 months is less than 90% or unknown, the
use of DOT should be expanded. If greater than or equal to 90% of
patients beginning therapy complete a recommended course of therapy
within 12 months, the expanded use of DOT may not be necessary.
However, even in these circumstances, consideration should be given
to extending the use of DOT to increase the treatment completion
rate. All patients with TB caused by organisms resistant to either
INH or RIF and all patients receiving intermittent therapy should
receive DOT.

DOT programs increase adherence in both rural and urban
settings and provide effective treatment for TB (12, 13). A
hospital in New York City reported that only 11% of patients under
care for TB reported to an outpatient clinic for further treatment
when discharged from the hospital (14). In contrast, a program in
which DOT is routinely used for all patients had a completion rate
of 98% (15).

Although expanding the use of DOT may require additional
resources, intermittent, directly observed regimens are cost
effective (16) (CDC unpublished data). DOT can be conducted with
regimens given once a day, 2 times/week, or 3 times/week.

When TB is initially diagnosed, medical providers should
explain to the patient about the disease, treatment, and the
importance of completing the recommended course of therapy. Medical
providers should also verify that the patient understands this
information. When DOT is administered, the method must be
specifically defined for each patient and be based on a thorough
assessment of each patient's needs, living/employment conditions,
and preferences. The patient and the provider should agree on a
method that ensures the best possible DOT routine and maintains
confidentiality. Patients who receive daily therapy can be
successfully managed with self-administered therapy. Public health
officials responsible for TB treatment should be notified when
patients not receiving DOT miss appointments or demonstrate other
nonadherent behaviors. These patients should be placed on DOT, and
all regimens administered 2 times/week or 3 times/week should be
administered as DOT for the duration of therapy.

Effective use of DOT sometimes requires an outreach worker to
go into the community to locate a patient and administer each dose
of medication. However, most patients can receive the daily, 2
times/week, or 3 times/ week treatment at a location agreed on by
both the provider and the patient. DOT can be arranged and
administered in various settings, including TB clinics, community
health centers, migrant clinics, homeless shelters, prisons or
jails, nursing homes, schools, drug treatment centers, hospitals,
HIV/AIDS clinics or hostels, or occupational health clinics.

In some situations, another responsible person other than a
health-care worker may administer DOT. Persons administering DOT
may include physicians, nurses, health care aides, nursing home
staff, correctional facility personnel, staff of community-based
organizations, school nurses or teachers, reliable volunteers, drug
treatment center employees, social and welfare caseworkers, and
clergy or other community leaders. These arrangements require
careful supervision by the medical provider. The use of incentives
or enablers (e.g., providing transportation or car/bus fare to the
DOT site) may promote patient adherence to a DOT program. The use
of combined preparations of INH and RIF (e.g., Rifamate Registered)
or INH, RIF, and PZA (not available in the United States) may also
improve patient adherence.

Poor patient adherence is a multifaceted problem; additional
research is needed to clarify the role of operational,
environmental, behavioral, and other factors in determining
adherence. A research agenda is described in "Problem 38" of the
National Action Plan to Combat Multidrug-Resistant Tuberculosis
(17).

CONCLUSION

These recommendations update previous CDC/American Thoracic
Society (ATS) recommendations for the treatment of TB among adults
and children (1). The ATS Statements Committee is revising that
previous report with representatives from CDC, the American Academy
of Pediatrics, and the Infectious Disease Society of America and
may offer similar recommendations. Questions concerning these
recommendations should be made to: CDC, National Center for
Prevention Services, Division of TB Elimination, Clinical Research
Branch, 1600 Clifton Road, MS E-10, Atlanta, GA 30333, (404)
639-2530.

7. Hong Kong Chest Service/British Medical Research Council.
Controlled trial of 4 three-times-weekly regimens and a daily
regimen given for 6 months for pulmonary TB. Second report: the
results of final results up to 24-months. Tubercle 1982;63:89.

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